146137-49-7Relevant academic research and scientific papers
The synthesis of gem-cyclopentyl substituted glutarates via the oxidative ring contraction of 2-acetylcyclohexanones
Challenger, Stephen,Derrick, Andrew,Silk, Terry V.
, p. 2911 - 2918 (2002)
A two step synthesis of differentially protected gem-cyclopentyl glutarates has been developed from 2-acetylcyclohexanone and acrylates. The key step involves an oxidative ring contraction reaction with hydrogen peroxide. The methodology has been used to
Design, synthesis and antihypertensive evaluation of novel codrugs with combined angiotensin type 1 receptor antagonism and neprilysin inhibition
Mascarello, Alessandra,Azevedo, Hatylas,Ferreira Junior, Marcos Antonio,Ishikawa, Eloisa Eriko,Guimar?es, Cristiano Ruch Werneck
, (2021/02/03)
The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.
Preparation of glutaric acid derivatives
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, (2008/06/13)
The invention provides a process for preparing a compound of the formula: STR1 or a base salt thereof, wherein R2 is hydrogen or C1 -C6 alkyl optionally substituted by up to 3 substituents each independently selected from
